Inorganic Chemistry
Article
ESI-MS (positive-ion mode). Calcd for C9H18N2O4Na ([M + Na]+):
m/z 241.09. Found: 241.07 (100%).
3-[6-Amino-N-(benzyloxy)hexanamido]propanoic Acid Trifluoro-
acetic Acid (4a). TFA (1 mL) was added to a solution of 3a (219 mg,
0.45 mmol) in DCM (4 mL). The solution mixture was stirred for 6 h
at room temperature under N2. The reaction mixture was concentrated
in vacuo to give an orange gum (187 mg, 100%). 1H NMR (400 MHz,
CD3OD): δ 7.37−7.43 (m, 5H), 4.87 (s, 2H), 3.96−3.99 (m, 2H),
2.89 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H), 2.39 (t, J = 7.2 Hz,
2H), 1.52−1.66 (m, 4H), 1.29−1.37 (m, 2H). 13C NMR (101 MHz,
CD3OD): δ 176.8, 175.0, 135.9, 130.7, 130.0, 129.7, 77.2, 42.3, 40.5,
32.9, 32.6, 28.2, 26.9, 24.9. ESI-MS (positive-ion mode). Calcd for
C26H42N2O6Na ([M + Na]+): m/z 501.29. Found: m/z 501.21
(100%).
3-[7-Amino-N-(benzyloxy)heptanamido]propanoic Acid Tri-
fluoroacetic Acid (4b). 3b (215 mg, 0.42 mmol) was treated with
20% TFA in DCM (5 mL) following the procedure outlined for 4a.
The title compound was obtained as a yellow gum (185 mg, 100%).
1H NMR (400 MHz, CD3OD): δ 7.37−7.44 (m, 5H), 4.89 (s, 2H),
4-[(5-Aminopentyl)(hydroxy)amino]-4-oxobutanoic-2,2,3,3-d4
Acid (for-PBH-d4). 4-[Benzyloxy[4-(benzyloxycarbonyl)pentyl]-
amino]-4-oxo-2,2,3,3-d4-butanoic acid (61 mg, 0.14 mmol; Schemes
S1 and S12 in the SI) was treated with 10% Pd/C (12 mg) following
the method described for the preparation of for-PBH. The title
compound was obtained as a white solid (28 mg, 92%). 1H NMR (400
MHz, CD3OD): δ 3.65 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H),
1.62−1.70 (m, 4H), 1.35−1.43 (m, 2H). 13C NMR (101 MHz,
CD3OD): δ 181.0, 175.4, 47.9, 40.5, 28.0, 26.8, 24.0. ESI-MS
(positive-ion mode). Calcd for C9H15D4N2O4 ([M + H]+): m/z
223.09. Found: m/z 223.07 (100%).
4-[(6-Aminohexyl)(hydroxy)amino]-4-oxobutanoic Acid (for-
HBH). 4-[Benzyloxy[7-[(benzyloxycarbonyl)amino]heptyl]amino]-4-
oxobutanoic acid (41 mg, 0.09 mmol; Schemes S1 and S10 in the
SI) was treated with 10% Pd/C (10 mg) following the method
described for the preparation of for-PBH. The title compound was
obtained as a white solid (20 mg, 97%). 1H NMR (400 MHz,
CD3OD): δ 3.63 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.67 (t, J
= 7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 1.59−1.70 (m, 4H), 1.30−1.45
(m, 4H). 13C NMR (101 MHz, CD3OD): δ 180.9, 175.2, 47.7, 40.2,
34.3, 29.5, 28.3, 27.2, 26.3. ESI-MS (positive-ion mode). Calcd for
C10H21N2O4 ([M + H]+): m/z 233.14. Found: m/z 232.80 (100%).
5-[(5-Aminopentyl)(hydroxy)amino]-5-oxopentanoic Acid (for-
PPH). 5-[Benzyloxy[5-[(benzyloxycarbonyl)amino]pentyl]amino]-5-
oxopentanoic acid (58 mg, 0.13 mmol; Schemes S1 and S11 in the
SI) was treated with 10% Pd/C (12 mg) following the method
described for the preparation of for-PBH. The title compound was
obtained as a white solid (29 mg, 98%). 1H NMR (400 MHz,
CD3OD): δ 3.64 (t, J = 6.4 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.53 (t, J
= 7.2 Hz, 2H), 2.08 (t, J = 7.2 Hz, 2H), 1.85−1.93 (m, 2H), 1.64−1.72
(m, 4H), 1.36−1.44 (m, 2H). 13C NMR (101 MHz, CD3OD): δ
181.9, 175.8, 48.3, 40.6, 38.2, 32.8, 28.1, 27.1, 24.4, 23.0. ESI-MS
(positive-ion mode). Calcd for C10H21N2O4 ([M + H]+): m/z 233.14.
Found: m/z 233.27 (100%).
tert-Butyl 3-[N-(Benzyloxy)-6-[(tert-butoxycarbonyl)amino]-
hexanamido]propanoate (3a). 1 (2.43 g, 9.72 mmol), 2a (1.87 g,
8.10 mmol), EDC (1.84 g, 9.72 mmol), HOBt (1.30 g, 9.72 mmol),
and DIPEA (6.79 mL, 38.88 mmol) were dissolved in DMF (15 mL)
and stirred for 24 h. The reaction mixture was diluted with DCM (50
mL) and washed with saturated NaHCO3 (50 mL), water (50 mL),
and brine (50 mL). The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified using flash
chromatography, eluting with 25% ethyl acetate in hexane to give a
clear gum (3.17 g, 84%). 1H NMR (400 MHz, CDCl3): δ 4.70 (s, 2H),
4.62 (bs, 1H), 3.78−3.81 (m, 2H), 2.94−2.99 (m, 2H), 2.40 (t, J = 6.8
Hz, 2H), 2.22 (t, J = 6.8 Hz, 2H), 1.42−1.49 (m, 2H), 1.30−1.37 (m,
11H), 1.30 (s, 9H), 1.13−1.20 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 175.2, 170.9, 156.1, 134.4, 129.4, 129.0, 128.7, 80.9, 79.0,
76.3, 41.5, 40.4, 33.2, 32.3, 29.8, 28.5, 28.0, 26.5, 24.1. ESI-MS
(positive-ion mode). Calcd for C25H40N2O6Na ([M + Na]+): m/z
487.29. Found: m/z 487.13 (100%).
tert-Butyl 3-[N-(Benzyloxy)-8-[(tert-butoxycarbonyl)amino]-
octanamido]propanoate (3b). 1 (155 mg, 0.62 mmol), 2b (138
mg, 0.56 mmol), HATU (300 mg, 0.78 mmol), and DIPEA (391 μL,
2.25 mmol) were dissolved in DMF (4 mL) and stirred for 16 h. The
reaction mixture was diluted with DCM (50 mL) and washed with
saturated NaHCO3 (50 mL), water (50 mL), and brine (50 mL). The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified using flash chromatography, eluting
with 25% EtOAc/hexane to give a clear gum (3.17 g, 84%). 1H NMR
(400 MHz, CDCl3): δ 7.34−7.38 (m, 5H), 4.80 (s, 2H), 4.54 (bs, 1H),
3.89 (t, J = 6.8 Hz, 2H), 3.04−3.09 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H),
2.31 (t, J = 7.2 Hz, 2H), 1.34−1.60 (m, 22H), 1.90−1.31 (m, 4H). 13C
NMR (101 MHz, CDCl3): δ 175.5, 171.0, 156.1, 134.5, 129.4, 129.1,
128.8, 80.9, 79.1, 76.5, 41.7, 40.6, 33.3, 32.5, 30.0, 29.1, 28.6, 28.2,
26.7, 24.5. ESI-MS (positive-ion mode). Calcd for C25H40N2O6Na
([M + Na]+): m/z 487.29. Found: m/z 486.93 (100%).
3.98 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 6.8 Hz,
2H), 2.38 (t, J = 6.8 Hz, 2H), 1.49−1.68 (m, 4H), 1.30−1.40 (m, 4H).
13C NMR (101 MHz, CD3OD): δ 177.1, 175.0, 136.0, 130.8, 130.0,
129.7, 77.2, 42.3, 40.6, 32.7, 29.6, 28.3, 27.1, 25.3, 24.2.
3-(6-Amino-N-hydroxyhexanamido)propanoic Acid (ret-PBH).
ret-PBH was synthesized, based on the literature for the preparation
of similar ligands.52 To a solution of 4a (330 mg, 0.99 mmol) in 1:9
(v/v) ethyl acetate/tert-butanol (30 mL) was added 10% Pd/C (60
mg). The mixture was stirred under a hydrogen atmosphere (1 atm)
for 3 h. The catalyst was filtered and washed with 1:1 (v/v) water/
methanol (20 mL), and the filtrate was concentrated in vacuo to give a
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white solid (230 mg, 94%). H NMR (400 MHz, CD3OD): δ 3.86−
3.90 (m, 2H), 2.92 (t, J = 7.6 Hz, 2H), 2.58−2.64 (m, 2H), 2.48−2.52
(m, 2H), 1.61−1.72 (m, 4H), 1.39−1.46 (m, 2H). 13C NMR (101
MHz, CD3OD): δ 175.8, 175.1, 45.2, 40.5, 32.8, 32.4, 28.3, 27.0, 25.0.
ESI-MS (positive-ion mode). Calcd for C9H19N2O4 ([M + H]+): m/z
219.13. Found: m/z 219.13 (100%).
3-(7-Amino-N-hydroxyheptanamido)propanoic Acid (ret-HBH).
ret-HBH was prepared based on the method for ret-PBH, with 7-
aminoheptanoic acid replacing 6-aminohexamoic acid. To a solution of
4b (92 mg, 0.27 mmol) in 1:9 (v/v) ethyl acetate/tert-butanol (9 mL)
was added 10% Pd/C (20 mg). The mixture was stirred under a
hydrogen atmosphere (1 atm) for 3 h. The catalyst was filtered and
washed with 1:1 (v/v) water/methanol (20 mL), and the filtrate was
1
concentrated in vacuo to give a white solid (81 mg). H NMR (400
MHz, CD3OD): δ 3.71 (t, J = 7.6 Hz, 2H), 2.90−2.94 (m, 2H), 2.60
(t, J = 7.2 Hz, 2H), 2.48 (t, J = 7.6 Hz, 2H), 1.59−1.70 (m, 4H), 1.36−
1.46 (m, 4H). 13C NMR (101 MHz, CD3OD): δ 177.5, 40.7, 34.7,
29.6, 28.3, 27.1, 25.7, 24.2. ESI-MS (positive-ion mode). Calcd for
C10H21N2O4 ([M + H]+): m/z 233.14. Found: m/z 233.33 (100%).
MTS Reactions: General Protocol. The multistep synthesis and
purification of the ligands furnished about 10−15 mg of material of
sufficient purity to proceed to the MTS reaction. This constrained the
scale of the MTS reactions and allowed analytical characterization of
reaction solutions. A methanol solution (5 mL) containing 10 mg of a
given endo-hydroxamic acid monomer (0.046 mmol, for-PBH, for-
PBH-d4, and ret-PBH; 0.043 mmol, for-HBH, ret-HBH, and for-PPH)
1
and /3 equiv of M(acac)3 [M = iron(III), for-PBH, for-PBH-d4, and
ret-PBH; M = gallium(III), for-PBH, for-PBH-d4, ret-PBH, for-HBH,
ret-HBH, and for-PPH] or Fe(NO3)3·9H2O (for-HBH, ret-HBH, and
for-PPH) was stirred at room temperature for 1 h. The solvent was
removed, and after drying over P2O5, the dark-orange [iron(III)] or
pale-yellow [gallium(III)] residue (∼14 mg) was dissolved in DMF
(10 mL), to which was added a 1:1 mixture of TEA (0.09 mmol) and
DPPA (0.09 mmol). After the reaction mixture was stirred at room
temperature under N2 for 7 days, the solvent was removed, and the
residue was prepared as a 10 mg mL−1 solution in methanol for
analysis using ESI-MS, RP-HPLC, and LC−MS.
Calculations: MM. Structures of for-PBH and ret-PBH with a
trans-configured hydroxamic acid group were built in HyperChem69
and minimized using the AMBER force field. The positions of two
water molecules, placed proximal to the hydrogen-bond donor and
acceptor atoms of the hydroxamic acid group [N(OH) and C(O)],
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Inorg. Chem. 2015, 54, 3573−3583